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Definitions

• the present invention is related to compounds having P2X7 modulating properties, pharmaceutical compositions comprising these compounds, chemical processes for preparing these compounds and their use in the treatment of diseases associated with P2X7 receptor activity in animals, in particular humans.
• the P2X7 receptor is a ligand-gated ion channel and is present on a variety of cell types, largely those known to be involved in the inflammatory and/or immune process, specifically, macrophages and monocytes in the periphery and predominantly in glial cells (microglia and astrocytes) of the CNS.
• macrophages and monocytes in the periphery and predominantly in glial cells (microglia and astrocytes) of the CNS.
• Activation of the P2X7 receptor by extracellular nucleotides leads to the release of proinflammatory cytokines IL-1 ⁇ and IL-18 (Muller, et. Al. Am. J. Respir. Cell Mol. Biol. 2011, 44, 456-464), giant cell formation (macrophages/microglial cells), degranulation (mast cells) and L-selectin shedding (lymphocytes) (Ferrari et al., J. Immunol. 2006, 176, 3877-3883; Surprenant and North, Annu. Rev. Physiol. 2009, 71, 333-359).
• P2X7 receptors are also located on antigen-presenting cells (keratinocytes, salivary acinar cells (parotid cells)), hepatocytes, erythrocytes, erythroleukaemic cells, monocytes, fibroblasts, bone marrow cells, neurones, and renal mesangial cells.
• antigen-presenting cells keratinocytes, salivary acinar cells (parotid cells)
• hepatocytes erythrocytes, erythroleukaemic cells, monocytes, fibroblasts, bone marrow cells, neurones, and renal mesangial cells.
• P2X7 knockout mice demonstrate the role of P2X7 in the development and maintenance of pain, as these mice are protected from the development of both adjuvant-induced inflammatory pain and partial nerve ligation-induced neuropathic pain (Chessell et al., Pain 2005, 114, 386-396).
• P2X7 knockout mice also exhibit an anti-depressant phenotype based on reduced immobility in forced swim and tail suspension tests (Basso et al., Behav. Brain Res. 2009, 198, 83-90.).
• P2X7 pathway is linked to the release of the pro-inflammatory cytokine, IL-1 ⁇ , which has been linked to precipitation of mood disorders in humans (Dantzer, Immunol. Allergy Clin. North Am. 2009, 29, 247-264; Capuron and Miller, Pharmacol. Ther. 2011, 130, 226-238).
• IL-1 ⁇ pro-inflammatory cytokine
• P2X7 was upregulated around amyloid plaques indicating a role of this target in such pathology as well (Parvathenani et al., J. Biol. Chem. 2003, 278, 13309-13317).
• the compounds of Formula (I) are compounds selected from those species described or exemplified in the detailed description below.
• the invention relates to enantiomers and diastereomers of the compounds of Formula I, as well as the pharmaceutically acceptable salts.
• the invention relates to pharmaceutical compositions for treating a disease, disorder, or medical condition mediated by P2X7 receptor activity, comprising an effective amount of at least one compound selected from compounds of Formula (I), pharmaceutically acceptable salts of compounds of Formula (I), pharmaceutically acceptable prodrugs of compounds of Formula (I), and pharmaceutically active metabolites of Formula (I).
• compositions according to the invention may further comprise one or more pharmaceutically acceptable excipients.
• the chemical embodiments of the present invention are useful as P2X7 receptor modulators.
• the invention is directed to a method for modulating P2X7 receptor activity, including when such receptor is in a subject, comprising exposing P2X7 receptor to an effective amount of at least one compound selected from compounds of Formula (I), pharmaceutically acceptable salts of compounds of Formula (I), pharmaceutically acceptable prodrugs of compounds of Formula (I), and pharmaceutically active metabolites of compounds of Formula (I).
• the invention is directed to a method of treating a subject suffering from, or diagnosed with a disease, disorder, or medical condition mediated by P2X7 receptor activity, comprising administering to the subject in need of such treatment an effective amount of at least one compound selected from compounds of Formula (I), pharmaceutically acceptable salts of compounds of Formula (I), pharmaceutically acceptable prodrugs of compounds of Formula (I), and pharmaceutically active metabolites of compounds of Formula (I). Additional embodiments of methods of treatment are set forth in the detailed description.
• the method of studying isotopically labeled compounds in metabolic studies (preferably with 14 C), reaction kinetic studies (with, for example 2 H or 3 H), detection or imaging techniques [such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT)] including drug or substrate tissue distribution assays, or in radioactive treatment of patients.
• detection or imaging techniques such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT)
• PET positron emission tomography
• SPECT single-photon emission computed tomography
• an 18 F or 11 C labeled compound may be particularly preferred for PET or SPECT studies.
• An object of the present invention is to overcome or ameliorate at least one of the disadvantages of the conventional methodologies and/or prior art, or to provide a useful alternative thereto.
• Additional embodiments of this invention include methods of making compounds of Formula (I), pharmaceutically acceptable salts of compounds of Formula (I), pharmaceutically acceptable prodrugs of compounds of Formula (I), and pharmaceutically active metabolites of Formula (I).
• R 1 is halo.
• R 1 is C 1 -C 3 alkyl.
• R 2 is C 1 -C 3 perhaloalkyl.
• R 2 is halo.
• R 3 is H.
• R 1 is halo
• R 2 is C 1 -C 3 perhaloalkyl
• R 3 is H.
• R 1 , R 2 , and R 3 are halo.
• R 1 and R 3 are halo and R 2 is H.
• R 1 and R 2 are halo and R 3 is H.
• R 4 is halo and R 5 is C 1 -C 3 perhaloalkyl.
• R 6 and R 7 are H and R 8 is OCH 3 .
• R 6 , R 7 and R 8 are H.
• R 9 , R 10 and R 12 are H and R 11 is F.
• R 1 and R 2 are Cl, R c is CH 3 , R b is
• R d , R e , R 3 , R 6 , R 7 and R 8 are H.
• R 1 and R 2 are Cl, R d is CH 3 , R b is
• R c , R e , R 3 , R 9 , R 10 and R 12 are H and R 11 is F.
• R 1 is Cl, and R 2 is CF 3 , R d is CH 3 , R b is
• R c , R e , R 3 , R 9 , R 19 and R 12 are H and R 11 is F.
• R 1 and R 2 are Cl, R d is CH 3 , R b is
• R 8 is OCH 3 , R c , R e , R 3 , R 6 , and R 7 are H.
• R 1 is Cl, and R 2 is CF 3 , R d is CH 3 , R c is
• R b is
• R d , R e , and R 3 are H.
• R 1 is Cl, and R 2 is CF 3 , R d is CH 3 , R c is
• R b is
• R d , R e , and R 3 are H.
• R 1 is Cl, and R 2 is CF 3 , R d is CH 3 , R c is
• R b is
• R d , R e , and R 3 are H.
• An additional embodiment of the invention is a pharmaceutical composition comprising and effective amount of at least one compound in Table 1 and at least one pharmaceutically acceptable excipient.
• enantiomers and diastereomers of the compounds of Formula I are enantiomers and diastereomers of the compounds of Formula I.
• pharmaceutically acceptable salts of the compounds of Formula I as well as the pharmaceutically acceptable salts of the enantiomers and diastereomers of the compounds of Formula I.
• isotopic variations of compounds of Formula I such as, e.g., deuterated compounds of Formula I.
• An additional embodiment of the invention is a method of treating a subject suffering from or diagnosed with a disease, disorder, or medical condition mediated by P2X7 receptor activity, comprising administering to a subject in need of such treatment an effective amount of at least one compound selected from compounds of Formula (I):
• the disease, disorder, or medical condition is selected from: diseases of the autoimmune and inflammatory system (Arulkumaran, N. et al. Expert Opin. Invetig Drugs, 2011, July; 20(7):897-915)
• diseases of the autoimmune and inflammatory system include rheumatoid arthritis, osteoarthritis, interstitial cystitis (Martins J P, et. al., Br J Pharmacol. 2012 January; 165(1):183-96), psoriasis (Killeen, M. E., et al., J Immunol. 2013 Apr.
• diseases of the nervous and neuro-immune system include acute and chronic pain (examples of acute and chronic pain include neuropathic pain, inflammatory pain, migraine, spontaneous pain (examples of spontaneous pain include opioid induced pain, diabetic neuropathy, postherpetic neuralgia, low back pain, chemotherapy-induced neuropathic pain, fibromyalgia) (Romagnoli, R, et.
• Examples of diseases involved with, and without, neuroinflammation of the Central Nervous System include mood disorders (examples of mood disorders include major depression, major depressive disorder, treatment resistant depression, bipolar disorder, anxious depression, anxiety) (Friedle, S A, et. al., Recent Patents on CNS Drug Discovery, 2010, 5, 35-45, Romagnoli, R, et. al., 2008), cognition, sleep disorders, multiple sclerosis (Sharp A J, et. al., J Neuroinflammation. 2008 Aug.
• Alzheimer's disease Diaz-Hernandez J I, et. al., Neurobiol Aging. 2012 August; 33(8):1816-28, Delarasse C, J Biol Chem. 2011 Jan. 28; 286(4):2596-606, Sanz J M, et. al., J Immunol. 2009 Apr. 1; 182(7):4378-85), Huntington's disease (Diaz-Hernández M, et. Al., FASEB J. 2009 June; 23(6):1893-906), Amyotrophic Lateral Sclerosis, autism, spinal cord injury,cerebral ischemia/traumatic brain injury (Chu K, et. al., J Neuroinflammation. 2012 Apr. 18; 9:69, Arbeloa J, et. al, Neurobiol Dis. 2012 March; 45(3):954-61) and stress-related disorders].
• P2X7 intervention may be beneficial in diseases of the cardiovascular, metabolic, gastrointestinal and urogenital systems
• diseases of the cardiovascular, metabolic, gastrointestinal and urogenital systems include diabetes ( Arterioscler Thromb Vasc Biol. 2004 July; 24(7):1240-5, J Cell Physiol. 2013 January; 228(1):120-9), diabetes mellitus, thrombosis (Furlan-Freguia C, et. al., J Clin Invest. 2011 July; 121(7):2932-44, Vergani, A. et al., Diabetes, 2013, 62, 1665-1675), irritable bowel disease, irritable bowel syndrome, ( J Immunol. 2011 Aug.
• cardiovascular diseases examples include hypertension (Ji X, et. al., Am J Physiol Renal Physiol. 2012 October; 303(8):F1207-15), myocardial infarction, ischemic heart disease, ischemia) ureteric obstruction, lower urinary tract syndrome ( Br J Pharmacol. 2012 January; 165(1):183-96), lower urinary tract dysfunction such as incontinence, and disease after cardiac transplant (Vergani, A. et al., Circulation. 2013; 127:463-475)].
• P2X7 antagonism may also present a novel therapeutic strategy for skeletal disorders, (examples of skeletal disorders include osteoporosis/osteopetrosis) and may also modulate secretory function of exocrine glands.
• modulation of the P2X7 receptor may also be beneficial in conditions such as: glaucoma, Glomerulonephritis, Chaga's Disease, chlamydia, neuroblastoma, Tuberculosis, Polycystic Kidney Disease, cancer, and acne (Thiboutot, D. M. J Investigative Dermatology, 2014, 134, 595-597).
• An additional embodiment of the invention is a method of treating a subject suffering from or diagnosed with a disease, disorder, or medical condition mediated by P2X7 receptor activity, wherein the disease, disorder, or medical condition is selected from the group consisting of: diseases of the autoimmune and inflammatory system [examples of diseases of the autoimmune and inflammatory system include rheumatoid arthritis, osteoarthritis, interstitial cystitis, psoriasis, septic shock, sepsis, allergic dermatitis, asthma (examples of asthma include allergic asthma, mild to severe asthma, and steroid resistant asthma), idiopathic pulmonary fibrosis, allergic rhinitis, chronic obstructive pulmonary disease and airway hyper-responsivenes]; diseases of the nervous and neuro-immune system [examples of diseases of the nervous and neuro-immune system include acute and chronic pain (examples of acute and chronic pain include neuropathic pain, inflammatory pain, migraine, spontaneous pain (examples of
• An additional embodiment of the invention is a method of treating a subject suffering from or diagnosed with a disease, disorder, or medical condition mediated by P2X7 receptor activity wherein the disease, disorder or medical condition is a disease involved with, and without, neuroinflammation of the Central Nervous System (CNS).
• CNS Central Nervous System
• An additional embodiment of the invention is a method of treating a subject suffering from or diagnosed with a disease involved with, and without, neuroinflammation of the Central Nervous System (CNS) wherein the disease, disorder or medical condition is a mood disorder.
• CNS Central Nervous System
• An additional embodiment of the invention is a method of treating a subject suffering from a mood disorder wherein the mood disorder is treatment resistant depression.
• alkyl refers to a straight- or branched-chain alkyl group having from 1 to 12 carbon atoms in the chain.
• alkyl groups include methyl (Me, which also may be structurally depicted by the symbol, “/”), ethyl (Et), n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl (tBu), pentyl, isopentyl, tert-pentyl, hexyl, isohexyl, and groups that in light of the ordinary skill in the art and the teachings provided herein would be considered equivalent to any one of the foregoing examples.
• C 1 -C 3 alkyl refers to a straight- or branched-chain alkyl group having from 1 to 3 carbon atoms in the chain.
• C 1 -C 4 alkyl refers to a straight- or branched-chain alkyl group having from 1 to 4 carbon atoms in the chain.
• alkoxy includes a straight chain or branched alkyl group with a terminal oxygen linking the alkyl group to the rest of the molecule.
• Alkoxy includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, pentoxy and so on.
• alkalkoxy refers to the group alkyl-O-alkyl, where alkyl is defined above. Such groups include methylenemethoxy (—CH 2 OCH 3 ) and ethylenemethoxy (—CH 2 CH 2 OCH 3 ).
• hydroxyl and “hydroxy” refer to an —OH group.
• cycloalkyl refers to a saturated carbocycle having from 3 to 6 ring atoms per carbocycle.
• Illustrative examples of cycloalkyl groups include the following entities, in the form of properly bonded moieties:
• C 3 -C 4 cycloalkyl refers to a saturated carbocycle having from 3 to 4 ring atoms.
• heterocycloalkyl refers to a monocyclic ring structure that is saturated and has from 4 to 6 ring atoms per ring structure selected from carbon atoms and one nitrogen atom.
• Illustrative entities, in the form of properly bonded moieties include:
• aryl refers to a monocyclic, aromatic carbocycle (ring structure having ring atoms that are all carbon) having 6 atoms per ring. (Carbon atoms in the aryl groups are sp 2 hybridized.)
• phenyl represents the following moiety:
• heteroaryl refers to a monocyclic or fused bicyclic heterocycle (ring structure having ring atoms selected from carbon atoms and up to four heteroatoms selected from nitrogen, oxygen, and sulfur) having from 3 to 9 ring atoms per heterocycle.
• heteroaryl groups include the following entities, in the form of properly bonded moieties:
• heteroaryl, cycloalkyl, aryl and heterocycloalkyl groups listed or illustrated above are not exhaustive, and that additional species within the scope of these defined terms may also be selected.
• cyano refers to the group —CN.
• halo represents chloro, fluoro, bromo or iodo.
• perhaloalkyl refers to a straight- or branched-chain alkyl group having from 1 to 4 carbon atoms in the chain optionally substituting hydrogens with halogens.
• perhaloalkyl groups include trifluoromethyl (CF 3 ), difluoromethyl (CF 2 H), monofluoromethyl (CH 2 F), pentafluoroethyl (CF 2 CF 3 ), tetrafluoroethyl (CHFCF 3 ),monofluoroethyl (CH 2 CH 2 F), trifluoroethyl (CH 2 CF 3 ), tetrafluorotrifluoromethylethyl (—CF(CF 3 ) 2 ), and groups that in light of the ordinary skill in the art and the teachings provided herein would be considered equivalent to any one of the foregoing examples.
• perhaloalkoxy refers to a straight- or branched-chain alkoxy group having from 1 to 4 carbon atoms in the chain optionally substituting hydrogens with halogens.
• perhaloalkoxy groups include trifluoromethoxy (OCF 3 ), difluoromethoxy (OCF 2 H), monofluoromethoxy (OCH 2 F), momofluoroethoxy (OCH 2 CH 2 F), pentafluoroethoxy (OCF 2 CF 3 ), tetrafluoroethoxy (OCHFCF 3 ), trifluoroethoxy (OCH 2 CF 3 ), tetrafluorotrifluoromethylethoxy (—OCF(CF 3 ) 2 ), and groups that in light of the ordinary skill in the art and the teachings provided herein would be considered equivalent to any one of the foregoing examples.
• substituted means that the specified group or moiety bears one or more substituents.
• unsubstituted means that the specified group bears no substituents.
• optionally substituted means that the specified group is unsubstituted or substituted by one or more substituents. Where the term “substituted” is used to describe a structural system, the substitution is meant to occur at any valency-allowed position on the system. In cases where a specified moiety or group is not expressly noted as being optionally substituted or substituted with any specified substituent, it is understood that such a moiety or group is intended to be unsubstituted.
• buffer solution or “buffer” solution are used herein interchangeably according to their standard meaning. Buffered solutions are used to control the pH of a medium, and their choice, use, and function is known to those of ordinary skill in the art. See, for example, G. D. Considine, ed., Van Nostrand's Encyclopedia of Chemistry, p. 261, 5 th ed. (2005), describing, inter alia, buffer solutions and how the concentrations of the buffer constituents relate to the pH of the buffer. For example, a buffered solution is obtained by adding MgSO 4 and NaHCO 3 to a solution in a 10:1 w/w ratio to maintain the pH of the solution at about 7.5.
• any formula given herein is intended to represent compounds having structures depicted by the structural formula as well as certain variations or forms.
• compounds of any formula given herein may have asymmetric centers and therefore exist in different enantiomeric forms. All optical isomers of the compounds of the general formula, and mixtures thereof, are considered within the scope of the formula.
• any formula given herein is intended to represent a racemate, one or more enantiomeric forms, one or more diastereomeric forms, one or more atropisomeric forms, and mixtures thereof.
• certain structures may exist as geometric isomers (i.e., cis and trans isomers), as tautomers, or as atropisomers.
• stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers.”
• enantiomers When a compound has an asymmetric center, for example, it is bonded to four different groups, and a pair of enantiomers is possible.
• An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R-and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+)- or ( ⁇ )-isomers respectively).
• a chiral compound can exist as either an individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture.”
• Tautomers refer to compounds that are interchangeable forms of a particular compound structure, and that vary in the displacement of hydrogen atoms and electrons. Thus, two structures may be in equilibrium through the movement of ⁇ electrons and an atom (usually H). For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base. Another example of tautomerism is the aci-and nitro-forms of phenyl nitromethane, that are likewise formed by treatment with acid or base.
• Tautomeric forms may be relevant to the attainment of the optimal chemical reactivity and biological activity of a compound of interest.
• Compounds of the invention may also exist as “rotamers,” that is, conformational isomers that occur when the rotation leading to different conformations is hindered, resulting in a rotational energy barrier to be overcome to convert from one conformational isomer to another.
• the compounds of this invention may possess one or more asymmetric centers; such compounds can therefore be produced as individual (R)- or (S)-stereoisomers or as mixtures thereof.
• Certain examples contain chemical structures that are depicted as an absolute enantiomer but are intended to indicate enatiopure material that is of unknown configuration.
• (R*) or (S*) is used in the name to indicate that the absolute stereochemistry of the corresponding stereocenter is unknown.
• a compound designated as (R*) refers to an enantiopure compound with an absolute configuration of either (R) or (S).
• the structures are named using (R) and (S).
• any formula given herein is intended to refer also to hydrates, solvates, and polymorphs of such compounds, and mixtures thereof, even if such forms are not listed explicitly.
• Certain compounds of Formula (I) or pharmaceutically acceptable salts of compounds of Formula (I) may be obtained as solvates.
• Solvates include those formed from the interaction or complexation of compounds of the invention with one or more solvents, either in solution or as a solid or crystalline form.
• the solvent is water and the solvates are hydrates.
• certain crystalline forms of compounds of Formula (I) or pharmaceutically acceptable salts of compounds of Formula (I) may be obtained as co-crystals.
• compounds of Formula (I) were obtained in a crystalline form.
• crystalline forms of compounds of Formula (I) were cubic in nature.
• pharmaceutically acceptable salts of compounds of Formula (I) were obtained in a crystalline form.
• compounds of Formula (I) were obtained in one of several polymorphic forms, as a mixture of crystalline forms, as a polymorphic form, or as an amorphous form.
• compounds of Formula (I) convert in solution between one or more crystalline forms and/or polymorphic forms.
• references to a compound herein stands for a reference to any one of: (a) the actually recited form of such compound, and (b) any of the forms of such compound in the medium in which the compound is being considered when named.
• reference herein to a compound such as R—COOH encompasses reference to any one of, for example, R—COOH (s) , R—COOH (sol) , and R—COO ⁇ (sol) .
• R—COOH (s) refers to the solid compound, as it could be for example in a tablet or some other solid pharmaceutical composition or preparation
• R—COOH (sol) refers to the undissociated form of the compound in a solvent
• R—COO ⁇ (sol) refers to the dissociated form of the compound in a solvent, such as the dissociated form of the compound in an aqueous environment, whether such dissociated form derives from R—COOH, from a salt thereof, or from any other entity that yields R—COO ⁇ upon dissociation in the medium being considered.
• an expression such as “exposing an entity to compound of formula R—COOH” refers to the exposure of such entity to the form, or forms, of the compound R—COOH that exists, or exist, in the medium in which such exposure takes place.
• an expression such as “reacting an entity with a compound of formula R—COOH” refers to the reacting of (a) such entity in the chemically relevant form, or forms, of such entity that exists, or exist, in the medium in which such reacting takes place, with (b) the chemically relevant form, or forms, of the compound R—COOH that exists, or exist, in the medium in which such reacting takes place.
• a zwitterionic compound is encompassed herein by referring to a compound that is known to form a zwitterion, even if it is not explicitly named in its zwitterionic form.
• Terms such as zwitterion, zwitterions, and their synonyms zwitterionic compound(s) are standard IUPAC-endorsed names that are well known and part of standard sets of defined scientific names.
• the name zwitterion is assigned the name identification CHEBI:27369 by the Chemical Entities of Biological Interest (ChEBI) dictionary of molecular entities.
• a zwitterion or zwitterionic compound is a neutral compound that has formal unit charges of opposite sign.
• aminoethanoic acid (the amino acid glycine) has the formula H 2 NCH 2 COOH, and it exists in some media (in this case in neutral media) in the form of the zwitterion + H 3 NCH 2 COO ⁇ .
• Zwitterions, zwitterionic compounds, inner salts and dipolar ions in the known and well established meanings of these terms are within the scope of this invention, as would in any case be so appreciated by those of ordinary skill in the art.
• any formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds.
• Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number.
• isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, 36 Cl, 125 I, respectively.
• Such isotopically labeled compounds are useful in metabolic studies (preferably with 14 C), reaction kinetic studies (with, for example 2 H or 3 H), detection or imaging techniques [such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT)] including drug or substrate tissue distribution assays, or in radioactive treatment of patients.
• PET positron emission tomography
• SPECT single-photon emission computed tomography
• an 18 F or 11 C labeled compound may be particularly preferred for PET or SPECT studies.
• substitution with heavier isotopes such as deuterium (i.e., 2 H) may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements.
• Isotopically labeled compounds of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.
• the invention includes also pharmaceutically acceptable salts of the compounds of Formula (I), preferably of those described above and of the specific compounds exemplified herein, and methods of treatment using such salts.
• pharmaceutically acceptable means approved or approvable by a regulatory agency of Federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U.S. Pharmcopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans.
• a “pharmaceutically acceptable salt” is intended to mean a salt of a free acid or base of compounds represented by Formula (I) that are non-toxic, biologically tolerable, or otherwise biologically suitable for administration to the subject. It should possess the desired pharmacological activity of the parent compound. See, generally, G. S. Paulekuhn, et al., “Trends in Active Pharmaceutical Ingredient Salt Selection based on Analysis of the Orange Book Database”, J. Med. Chem., 2007, 50:6665-72, S. M.
• a compound of Formula (I) may possess a sufficiently acidic group, a sufficiently basic group, or both types of functional groups, and accordingly react with a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.
• Examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen-phosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates, benzoates, chlorobenzoates, methyl benzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylenesulfonates, phenylacetates, phen
• the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art.
• an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, boric acid, phosphoric acid, and the like
• an organic acid such as acetic acid, phenylacetic acid, propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid, hydroxymaleic acid, isethionic acid, succinic acid, valeric acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, oleic acid, palmitic acid, lauric acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha-hydroxy acid, such as mandelic acid, citric acid, or tartaric acid, an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid,
• the desired pharmaceutically acceptable salt may be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), an alkali metal hydroxide, alkaline earth metal hydroxide, any compatible mixture of bases such as those given as examples herein, and any other base and mixture thereof that are regarded as equivalents or acceptable substitutes in light of the ordinary level of skill in this technology.
• an inorganic or organic base such as an amine (primary, secondary or tertiary), an alkali metal hydroxide, alkaline earth metal hydroxide, any compatible mixture of bases such as those given as examples herein, and any other base and mixture thereof that are regarded as equivalents or acceptable substitutes in light of the ordinary level of skill in this technology.
• suitable salts include organic salts derived from amino acids, such as N-methyl-D-glucamine, lysine, choline, glycine and arginine, ammonia, carbonates, bicarbonates, primary, secondary, and tertiary amines, and cyclic amines, such as tromethamine, benzylamines, pyrrolidines, piperidine, morpholine, and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.
• amino acids such as N-methyl-D-glucamine, lysine, choline, glycine and arginine
• ammonia carbonates, bicarbonates, primary, secondary, and tertiary amines
• cyclic amines such as tromethamine, benzylamines, pyrrolidines, piperidine, morpholine, and piperazine
• inorganic salts derived
• the invention also relates to pharmaceutically acceptable prodrugs of the compounds of Formula (I), and treatment methods employing such pharmaceutically acceptable prodrugs.
• prodrug means a precursor of a designated compound that, following administration to a subject, yields the compound in vivo via a chemical or physiological process such as solvolysis or enzymatic cleavage, or under physiological conditions (e.g., a prodrug on being brought to physiological pH is converted to the compound of Formula (I).
• a “pharmaceutically acceptable prodrug” is a prodrug that is non-toxic, biologically tolerable, and otherwise biologically suitable for administration to the subject. Illustrative procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in “ Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.
• Exemplary prodrugs include compounds having an amino acid residue, or a polypeptide chain of two or more (e.g., two, three or four) amino acid residues, covalently joined through an amide or ester bond to a free amino, hydroxyl, or carboxylic acid group of a compound of Formula (I, IIa or IIb).
• amino acid residues include the twenty naturally occurring amino acids, commonly designated by three letter symbols, as well as 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid, citrulline homocysteine, homoserine, ornithine and methionine sulfone.
• amides include those derived from ammonia, primary C 1-6 alkyl amines and secondary di(C 1-6 alkyl) amines. Secondary amines include 5- or 6-membered heterocycloalkyl or heteroaryl ring moieties. Examples of amides include those that are derived from ammonia, C 1-3 alkyl primary amines, and di(C 1-2 alkyl)amines.
• esters of the invention include C 1-7 alkyl, C 5-7 cycloalkyl, phenyl, and phenyl(C 1-6 alkyl) esters.
• Preferred esters include methyl esters.
• Prodrugs may also be prepared by derivatizing free hydroxy groups using groups including hemisuccinates, phosphate esters, dimethylaminoacetates, and phosphoryloxymethyloxycarbonyls, following procedures such as those outlined in Fleisher et al., Adv. Drug Delivery Rev. 1996, 19, 115-130. Carbamate derivatives of hydroxy and amino groups may also yield prodrugs.
• Carbonate derivatives, sulfonate esters, and sulfate esters of hydroxy groups may also provide prodrugs.
• Derivatization of hydroxy groups as (acyloxy)methyl and (acyloxy)ethyl ethers, wherein the acyl group may be an alkyl ester, optionally substituted with one or more ether, amine, or carboxylic acid functionalities, or where the acyl group is an amino acid ester as described above, is also useful to yield prodrugs.
• Prodrugs of this type may be prepared as described in Robinson et al., J Med Chem. 1996, 39 (1), 10-18. Free amines can also be derivatized as amides, sulfonamides or phosphonamides. All of these prodrug moieties may incorporate groups including ether, amine, and carboxylic acid functionalities.
• the present invention also relates to pharmaceutically active metabolites of the compounds of Formula (I), which may also be used in the methods of the invention.
• a “pharmaceutically active metabolite” means a pharmacologically active product of metabolism in the body of a compound of Formula (I, IIa or IIb) or salt thereof.
• Prodrugs and active metabolites of a compound may be determined using routine techniques known or available in the art. See, e.g., Bertolini, et al., J Med Chem. 1997, 40, 2011-2016; Shan, et al., J Pharm Sci. 1997, 86 (7), 765-767; Bagshawe, Drug Dev Res. 1995, 34, 220-230; Bodor, Adv Drug Res.
• the compounds of Formula (I) and their pharmaceutically acceptable salts, pharmaceutically acceptable prodrugs, and pharmaceutically active metabolites of the present invention are useful as modulators of the P2X7 receptor in the methods of the invention.
• the compounds may act as antagonists, agonists, or inverse agonists.
• modulators include both inhibitors and activators, where “inhibitors” refer to compounds that decrease, prevent, inactivate, desensitize, or down-regulate the P2X7 receptor expression or activity, and “activators” are compounds that increase, activate, facilitate, sensitize, or up-regulate P2X7 receptor expression or activity.
• treat is intended to refer to administration of an active agent or composition of the invention to a subject for the purpose of affecting a therapeutic or prophylactic benefit through modulation of P2X7 receptor activity. Treating includes reversing, ameliorating, alleviating, inhibiting the progress of, lessening the severity of, or preventing a disease, disorder, or condition, or one or more symptoms of such disease, disorder or condition mediated through modulation of P2X7 receptor activity.
• subject refers to a mammalian patient in need of such treatment, such as a human.
• the invention relates to methods of using the compounds described herein to treat subjects diagnosed with or suffering from a disease, disorder, or condition mediated by P2X7 receptor activity, such as: diseases of the autoimmune and inflammatory system [examples of diseases of the autoimmune and inflammatory system include rheumatoid arthritis, osteoarthritis, interstitial cystitis, psoriasis, septic shock, sepsis, allergic dermatitis, asthma (examples of asthma include allergic asthma, mild to severe asthma, and steroid resistant asthma), idiopathic pulmonary fibrosis, allergic rhinitis, chronic obstructive pulmonary disease and airway hyper-responsivenes]; diseases of the nervous and neuro-immune system [examples of diseases of the nervous and neuro-immune system include acute and chronic pain (examples of acute and chronic pain include neuropathic pain, inflammatory pain, migraine, spontaneous pain (examples of spontaneous pain include opioid induced pain, diabetic neuropathy, post
• an effective amount of a pharmaceutical agent according to the invention is administered to a subject suffering from or diagnosed as having such a disease, disorder, or condition.
• An “effective amount” means an amount or dose sufficient to generally bring about the desired therapeutic or prophylactic benefit in patients in need of such treatment for the designated disease, disorder, or condition.
• Effective amounts or doses of the compounds of the present invention may be ascertained by routine methods such as modeling, dose escalation studies or clinical trials, and by taking into consideration routine factors, e.g., the mode or route of administration or drug delivery, the pharmacokinetics of the compound, the severity and course of the disease, disorder, or condition, the subject's previous or ongoing therapy, the subject's health status and response to drugs, and the judgment of the treating physician.
• An example of a dose is in the range of from about 0.001 to about 200 mg of compound per kg of subject's body weight per day, preferably about 0.05 to 100 mg/kg/day, or about 1 to 35 mg/kg/day, in single or divided dosage units (e.g., BID, TID, QID).
• a suitable dosage amount is from about 0.05 to about 7 g/day, or about 0.2 to about 2.5 g/day.
• the dose may be adjusted for preventative or maintenance treatment.
• the dosage or the frequency of administration, or both may be reduced as a function of the symptoms, to a level at which the desired therapeutic or prophylactic effect is maintained.
• treatment may cease. Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of symptoms.
• the active agents of the invention may be used in combination with additional active ingredients in the treatment of the above conditions.
• the additional active ingredients may be coadministered separately with an active agent of compounds of Tables 1 or included with such an agent in a pharmaceutical composition according to the invention.
• additional active ingredients are those that are known or discovered to be effective in the treatment of conditions, disorders, or diseases mediated by P2X7 activity, such as another P2X7 modulator or a compound active against another target associated with the particular condition, disorder, or disease.
• the combination may serve to increase efficacy (e.g., by including in the combination a compound potentiating the potency or effectiveness of an active agent according to the invention), decrease one or more side effects, or decrease the required dose of the active agent according to the invention.
• a pharmaceutical composition of the invention comprises: (a) an effective amount of at least one active agent in accordance with the invention; and (b) a pharmaceutically acceptable excipient.
• a “pharmaceutically acceptable excipient” refers to a substance that is non-toxic, biologically tolerable, and otherwise biologically suitable for administration to a subject, such as an inert substance, added to a pharmacological composition or otherwise used as a vehicle, carrier, or diluent to facilitate administration of an agent and that is compatible therewith.
• excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.
• compositions containing one or more dosage units of the active agents may be prepared using suitable pharmaceutical excipients and compounding techniques known or that become available to those skilled in the art.
• the compositions may be administered in the inventive methods by a suitable route of delivery, e.g., oral, parenteral, rectal, topical, or ocular routes, or by inhalation.
• the preparation may be in the form of tablets, capsules, sachets, dragees, powders, granules, lozenges, powders for reconstitution, liquid preparations, or suppositories.
• the compositions are formulated for intravenous infusion, topical administration, or oral administration.
• the compounds of the invention can be provided in the form of tablets or capsules, or as a solution, emulsion, or suspension.
• the compounds may be formulated to yield a dosage of, e.g., from about 0.05 to about 100 mg/kg daily, or from about 0.05 to about 35 mg/kg daily, or from about 0.1 to about 10 mg/kg daily.
• a total daily dosage of about 5 mg to 5 g daily may be accomplished by dosing once, twice, three, or four times per day.
• Oral tablets may include a compound according to the invention mixed with pharmaceutically acceptable excipients such as inert diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavoring agents, coloring agents and preservative agents.
• suitable inert fillers include sodium and calcium carbonate, sodium and calcium phosphate, lactose, starch, sugar, glucose, methyl cellulose, magnesium stearate, mannitol, sorbitol, and the like.
• Exemplary liquid oral excipients include ethanol, glycerol, water, and the like.
• Starch, polyvinyl-pyrrolidone (PVP), sodium starch glycolate, microcrystalline cellulose, and alginic acid are suitable disintegrating agents.
• Binding agents may include starch and gelatin.
• the lubricating agent if present, may be magnesium stearate, stearic acid or talc. If desired, the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate to delay absorption in the gastrointestinal tract, or may be coated with an enteric coating.
• Capsules for oral administration include hard and soft gelatin capsules.
• compounds of the invention may be mixed with a solid, semi-solid, or liquid diluent.
• Soft gelatin capsules may be prepared by mixing the compound of the invention with water, an oil such as peanut oil or olive oil, liquid paraffin, a mixture of mono and di-glycerides of short chain fatty acids, polyethylene glycol 400, or propylene glycol.
• Liquids for oral administration may be in the form of suspensions, solutions, emulsions or syrups or may be lyophilized or presented as a dry product for reconstitution with water or other suitable vehicle before use.
• Such liquid compositions may optionally contain: pharmaceutically-acceptable excipients such as suspending agents (for example, sorbitol, methyl cellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel and the like); non-aqueous vehicles, e.g., oil (for example, almond oil or fractionated coconut oil), propylene glycol, ethyl alcohol, or water; preservatives (for example, methyl or propyl p-hydroxybenzoate or sorbic acid); wetting agents such as lecithin; and, if desired, flavoring or coloring agents.
• suspending agents for example, sorbitol, methyl cellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose,
• the active agents of this invention may also be administered by non-oral routes.
• the compositions may be formulated for rectal administration as a suppository.
• parenteral use including intravenous, intramuscular, intraperitoneal, or subcutaneous routes, the compounds of the invention may be provided in sterile aqueous solutions or suspensions, buffered to an appropriate pH and isotonicity or in parenterally acceptable oil.
• Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride.
• Such forms will be presented in unit-dose form such as ampules or disposable injection devices, in multi-dose forms such as vials from which the appropriate dose may be withdrawn, or in a solid form or pre-concentrate that can be used to prepare an injectable formulation.
• Illustrative infusion doses may range from about 1 to 1000 ⁇ g/kg/minute of compound, admixed with a pharmaceutical carrier over a period ranging from several minutes to several days.
• the compounds may be mixed with a pharmaceutical carrier at a concentration of about 0.1% to about 10% of drug to vehicle.
• a pharmaceutical carrier for topical administration, may be mixed with a pharmaceutical carrier at a concentration of about 0.1% to about 10% of drug to vehicle.
• Another mode of administering the compounds of the invention may utilize a patch formulation to affect transdermal delivery.
• Compounds of the invention may alternatively be administered in methods of this invention by inhalation, via the nasal or oral routes, e.g., in a spray formulation also containing a suitable carrier.
• the group PG represents a protecting group.
• One skilled in the art will select the appropriate protecting group compatible with the desired reactions.
• the protecting groups may be removed at a convenient subsequent stage using methods known from the art. Alternatively, it may be necessary to employ, in the place of the ultimately desired substituent, a suitable group that may be carried through the reaction scheme and replaced as appropriate with the desired substituent.
• Such compounds, precursors, or prodrugs are also within the scope of the invention.
• preferred protecting groups include; carbamates, benzyl and substituted benzyl groups. Especially preferred protecting groups are tert-butyloxycarbonyl and benzyl.
• Compound IA can be converted to compound IIA by reaction with Lawesson's reagent, in a solvent such as THF, diethyl ether or DCM. This reaction may be performed at room temperature or heated overnight at or near the boiling point of the solvent.
• Compound IIA may be converted to amine IIIA by treatment with an alkylating agent such as trimethyloxonium tetrafluoroborate or methyl iodide in a solvent such as DCM or DMF, at a temperature of between room temperature and 40° C. for between 1 and 48 hours.
• an alkylating agent such as trimethyloxonium tetrafluoroborate or methyl iodide in a solvent such as DCM or DMF
• Compound IVA may be converted to compound VA by treatment with hydrazine monohydrate in a solvent such as an alcohol, DCM or DMF at a temperature near room temperature for from 1 to 25 hours.
• Compound VIA may be converted to compound VIIA by treatment with an appropriate acylating agent such as oxalyl chloride in the presence of a catalyst such as DMF in a solvent such as DCM or DMF for from 1 to 8 hours.
• Compound VIIA may then also be converted to compound VA by treatment with hydrazine monohydrate in a solvent such as an alcohol, DCM or DMF at a temperature near room temperature for from 1 to 12 hours.
• compound VIAB may be converted to compound VIIAB by treatment with an appropriate acylating agent such as oxalyl chloride in the presence of a catalyst such as DMF in a solvent such as DCM or DMF for from 1 to 8 hours.
• an appropriate acylating agent such as oxalyl chloride
• a catalyst such as DMF in a solvent such as DCM or DMF
• a catalyst such as DMF
• a solvent such as DCM or DMF
• a catalyst such as DMF
• a solvent such as DCM or DMF
• VIA or VIAB can be directly formed from the halogen compound via metal halogen exchange followed by quenching with CO 2 .
• VIA or VIAB can also be formed by oxidation of a suitable methyl substituted compound with a reagent, such as, KMnO 4 and then IVA may be formed by subsequent esterification of VIA.
• a reagent such as, KMnO 4
• IVA may be formed by subsequent esterification of VIA.
• These compounds can also be formed by oxidation of an appropriately substituted hydroxymethyl compound in either one or two steps to afford VIA or VIAB.
• Compound IIIA may be converted to compound VIIIA by the addition of compound VA and a suitable base such as potassium t-butoxide in an alcohol solvent such as methanol. This reaction can be performed at a temperature from room temperature to 120° C. for from 30 minutes to 48 hours. Compound VIIIA can then be converted to compound IXA by addition of a suitable acid such as HCl or TFA, preferably TFA in a solvent such as DCM, DCE or dioxane. This reaction can be performed at a temperature from room temperature to 50° C. for from 30 minutes to 24 hours.
• a suitable acid such as HCl or TFA, preferably TFA in a solvent such as DCM, DCE or dioxane. This reaction can be performed at a temperature from room temperature to 50° C. for from 30 minutes to 24 hours.
• reaction mixtures were magnetically stirred at room temperature (rt) under a nitrogen atmosphere. Where solutions were “dried,” they were generally dried over a drying agent such as Na 2 SO 4 or MgSO 4 . Where mixtures, solutions, and extracts were “concentrated”, they were typically concentrated on a rotary evaporator under reduced pressure. Reactions under microwave irradiation conditions were carried out in a Biotage Initiator or CEM Corporation Discover instrument. Hydrogenations on the H-cube were run by passing solvent containing reactant through a catalyst cartridge on an H-Cube hydrogenation apparatus at a pressure of 15 to 100 bar and a flow rate of 1 to 30 ml/min.
• HPLC reverse-phase high performance liquid chromatography
• Mass spectra were obtained on an Agilent series 1100 MSD using electrospray ionization (ESI) in positive mode unless otherwise indicated. Calculated (calcd.) mass corresponds to the exact mass.
• Nuclear magnetic resonance (NMR) spectra were obtained on Bruker model DRX spectrometers.
• the format of the 1 H NMR data below is: chemical shift in ppm downfield of the tetramethylsilane reference (multiplicity, coupling constant J in Hz, integration).
• a notation of ( ⁇ ) or R/S indicates that the product is a racemic mixture of enantiomers and/or diastereomers.
• a notation of, for example, (2S, 3R) indicates that product stereochemistry depicted is based on the known stereochemistry of similar compounds and/or reactions.
• a notation of, for example, (2S*, 3R*) indicates that the product is a pure and single diastereomer but the absolute stereochemistry is not established and relative stereochemistry is shown.
• Step a tert-Butyl 2-methyl-3-oxopiperazine-1-carboxylate
• Step b tert-Butyl 8-methyl-3-(pyridin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-carboxylate
• step a 230 mg, 1.08 mmol
• DCM dimethyloxonium tetrafluoroborate
• 2-picolinyl hydrazide 181 mg, 1.29 mmol
• the reaction was concentrated in vacuo and dissolved in dioxane (2 mL) and saturated aqueous NaHCO 3 solution (2 mL). The mixture was heated for 3 h at 90° C. and the dioxane was removed in vacuo and the aqueous layer extracted with DCM and EtOAc.
• Step c 8-methyl-3-(pyridin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine
• step b (150 mg, 0.48 mmol) in DCM (2 mL) was added TFA (0.48 mL). After stirring 3 h, the reaction was concentrated in vacuo. The residue was redissolved in DCM and treated with Dowex 550A resin. The resin was removed by filtration and concentration afforded a white solid. Chromatography on SiO 2 eluting with 2M NH 3 in MeOH/DCM afforded the desired compound (100 mg, 98%). MS (ESI) mass calcd. C 11 H 13 N 5 , 215.12; m/z found 216.0 [M+H] + .
• Step d 7-[(2,3-Dichlorophenyl)carbonyl]-8-methyl-3-pyridin-2-yl-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine
• step c To a solution of the product of Example 1, step c (83 mg, 0.39 mmol) in DCM (4 mL) was added 2,4-dichlorobenzoic acid (74 mg, 0.39 mmol) followed by EDCI (111 mg, 0.58 mmol), HOBt (36 mg, 0.27 mmol) and TEA (0.11 mL, 0.77 mmol). The mixture was stirred overnight and then loaded directly on a column. Chromatography on SiO 2 eluting with EtOAc/Hex afforded impure material.
• Example 2 absolute configuration unknown, was obtained by chiral separation of Example 1 utilizing SFC.
• Example 2 was the second compound off the column (16 mg). MS (ESI) mass calcd. C 18 H 15 Cl 2 N 5 O, 387.07; m/z found 388.1 [M+H] + .
• 1H NMR 500 MHz, CDCl3): 8.67-8.53 (m, 1H), 8.37-8.29 (m, 1H), 7.87-7.80 (m, 1H), 7.59-7.54 (m, 1H), 7.38-7.23 (m, 3H), 6.24-6.17 (m, 0.5H), 5.23-4.89 (m, 2H), 4.43-4.10 (m, 1H), 3.74-3.61 (m, 1H), 3.59-3.32 (m, 0.5H), 1.85-1.55 (m, 3H).
• Example 3 absolute configuration unknown, was obtained by chiral separation of Example 1 utilizing SFC.
• Example 3 was the first compound off the column (16 mg). MS (ESI) mass calcd. C 18 H 15 Cl 2 N 5 O, 387.07; m/z found 388.1 [M+H] + .
• 1H NMR 500 MHz, CDCl3): 8.68-8.53 (m, 1H), 8.37-8.29 (m, 1H), 7.88-7.81 (m, 1H), 7.60-7.54 (m, 1H), 7.38-7.23 (m, 3H), 6.23-6.17 (m, 0.5H), 5.22-4.91 (m, 2H), 4.43-4.10 (m, 1H), 3.73-3.63 (m, 1H), 3.59-3.32 (m, 0.5H), 1.84-1.52 (m, 3H).
• Examples 4-11 can be made in a manner analogous to Example 1, substituting the appropriate starting materials for each step.
• Example 12 was isolated following chiral SFC separation of Example 11 on a CHIRALCEL OD-H 5 ⁇ m 250 ⁇ 20mm column with mobile phase consisting of 70% CO 2 , 30% MeOH. Example 12 was the first eluting peak under these conditions. MS (ESI): mass calcd. for C 19 H 16 Cl 2 N 4 O, 386.1; m/z found, 386.10 [M+H] + .
• Example 13 was isolated following chiral SFC separation of Example 11 on a CHIRALCEL OD-H 5 ⁇ m 250 ⁇ 20mm column with mobile phase consisting of 70% CO 2 , 30% MeOH. Example 13 was the second eluting peak under these conditions.
• Example 14 was isolated following chiral SFC separation of Example 10 on a CHIRALCEL OD-H 5 ⁇ m 250 ⁇ 20mm column with mobile phase consisting of 75% CO 2 , 25% MeOH. Example 14 was the first eluting peak under these conditions.
• Example 15 was isolated following chiral SFC separation of Example 10 on a CHIRALCEL OD-H 5 ⁇ m 250 ⁇ 20mm column with mobile phase consisting of 75% CO 2 , 25% MeOH.
• Example 14 was the second eluting peak under these conditions.
• Step A (S)-tert-butyl 6-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-carboxylate
• Step B (S)-tert-butyl 3-bromo-6-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-carboxylate
• Step C (S)-tert-butyl 3-(furan-2-yl)-6-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-carboxylate
• Step D (S)-(2-chloro-3-(trifluoromethyl)phenyl)(3-(furan-2-yl)-6-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone
• Step a tert-butyl 2-methyl-3-thioxopiperazine-1-carboxylate
• Step b tert-butyl 3-(4-fluorophenyl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-carboxylate
• step a 230 mg, 1.00 mmol
• 4-fluorobenzhydrazide (241 mg, 1.50 mmol) were added to a round bottom flask followed by n-BuOH (4 mL).
• the mixture was heated at 140° C. for 48 h.
• the mixture was concentrated in vacuo and taken on to the next step without further purification.
• MS (ESI) mass calcd. C 17 H 21 FN 4 O 2 , 332.16; m/z found 333.2 [M+H] + .
• Step c 3-(4-fluorophenyl)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine
• step b (332 mg, 1.00 mmol) in DCM (5 mL) was added TFA (2 mL). After stirring 2 h, the reaction was complete and concentrated in vacuo. The TFA salt was loaded on SiO 2 column eluting with 2 M NH 3 in MeOH/DCM over 1 h to afford the desired compound as a pale yellow solid. MS (ESI) mass calcd. C 12 H 13 FN 4 , 232.11; m/z found 233.1 [M+H] + .
• Step d 7- ⁇ [2-Chloro-3-(trifluoromethyl)phenyl]carbonyl ⁇ -3-(4-fluorophenyl)-8-methyl-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine
• step c 189 mg, 0.82 mmol
• DCM DCM
• 2-chloro-3-(trifluoromethyl)benzoyl chloride 208 mg, 0.86 mmol
• MS (ESI) mass calcd. C 20 H 15 ClF 4 N 4 O, 438.09; m/z found 439.1 [M+H] + .
• reaction mixture was diluted with EtOAc, washed with water, dried, concentrated and purified by flash column chromatography (0-100% EtOAc in hexanes) to provide (S)-tert-butyl 6-methyl-3-(4-(trifluoromethyl)phenyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-carboxylate (375 mg).
• Step A tert-butyl (2-(2-bromo-2-phenylacetamido)ethyl)carbamate
• Step B N-(2-aminoethyl)-2-bromo-2-phenylacetamide
• Step C tert-butyl 3-oxo-2-phenylpiperazine-1-carboxylate
• Step D tert-butyl 2-phenyl-3-thioxopiperazine-1-carboxylate
• Step E tert-butyl 3-(methylthio)-2-phenyl-5,6-dihydropyrazine-1(2H)-carboxylate
• Step F tert-butyl 3-methyl-8-phenyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-carboxylate
• Step G 3-methyl-8-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine
• Step H (2-chloro-3-(trifluoromethyl)phenyl)(3-methyl-8-phenyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone
• Trifluoroacetic acid (2.5 mL, 32.67 mmol) was added to a mixture of (S)-tert-butyl 3-(4-methoxy-2-pyridyl)-6-methyl-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazine-7-carboxylate (457 mg, 1.32 mmol) in CH 2 Cl 2 (2.5 mL). The solution was stirred for 15 min at room temperature and then the mixture was basified with aq. sat NaHCO 3 and extracted with CH 2 Cl 2 .
• the desired product was prepared in an analogous manner to example 53.
• the racemic product was separated via chiral SFC (Stationary phase: CHIRALPAK AD-H 5 ⁇ m 250 ⁇ 20 mm), (Mobile phase: 65% CO 2 , 35% iPrOH) yielding the desired product.
• 1 H NMR 400 MHz, CDCl 3 ) ⁇ 7.86-7.73 (m, 1H), 7.58-7.28 (m, 7H), 6.16-5.99; 5.21-5.05 (m, 1H), 4.16-3.31 (m, 4H), 2.53-2.40 (m, 3H).
• the desired product was prepared in an analogous manner to example 53.
• the racemic product was separated via chiral SFC (Stationary phase: CHIRALPAK AD-H 5 ⁇ m 250 ⁇ 20 mm), (Mobile phase: 65% CO 2 , 35% iPrOH) yielding the desired product.
• 1 H NMR 400 MHz, CDCl 3 ) ⁇ 7.84-7.74 (m, 1H), 7.58-7.28 (m, 7H), 6.15-5.99; 5.19-5.05 (m, 1H), 4.17-3.31 (m, 4H), 2.53-2.43 (m, 3H).
• MS (ESI) mass mass calcd. C 20 H 16 ClF 3 N 4 O, 420.1; m/z found, 421.0 [M+H] + .
• the residue was chromatographed (SiO 2 , 0-10% 2 N NH 3 in MeOH)/CH 2 Cl 2 ). After concentration in vacuo the resulting residue was dissolved in dry THF (0.2 mL) and tetrabutylammonium fluoride THF solution (0.041 mL, 0.041 mmol) was added. The reaction was heated to 120° C. for 5 min in the microwave. An additional 0.041 mmol TBAF was added and the reaction was heated in the microwave to 150° C. for 5 min, followed by 160° C. for 30 min and 165° C. for 40 min, and finally 160° C. for 90 min.
• reaction was purified by prep HPLC (C18 XSelect 19 ⁇ 100 5 ⁇ m, Mobile phase Gradient from 80% 0.1% NH 4 CO 3 H/NH 4 OH pH 9 solution in Water, 20% CH 3 CN to 0% 0.1% NH 4 CO 3 H/NH 4 OH pH 9 solution in Water, 100% CH 3 CN) 1.6 mg, 9.6%).
• MS (ESI) mass calcd. C 18 H 14 Cl 2 FN 5 O, 405.1; m/z found, 405.0.
• the reaction mixture was slowly warmed to room temperature and stirred for 30 additional min.
• the reaction mixture was quenched with water and extracted with CH 2 Cl 2 .
• the organic layers were separated, dried (Na 2 SO 4 ), filtered and the solvent concentrated in vacuo.
• the crude product was purified by column chromatography (silica, MeOH in EtOAc 0:100 to 10:90), the desired fractions were collected and the solvent evaporated in vacuo to yield the desired compound with some impurities. This was purified by RP HPLC on (C18 Sunfire 30 ⁇ 100 5 ⁇ m).
• the reaction mixture was slowly warmed to room temperature and stirred for 30 min.
• the reaction mixture was quenched with water and extracted with CH 2 Cl 2 .
• the organic layers were separated, dried (Na 2 SO 4 ), filtered and the solvent concentrated in vacuo.
• the crude product was purified twice by column chromatography (silica, MeOH in EtOAc 0:100 to 10:90), the desired fractions were collected and the solvent evaporated in vacuo. Final purification was performed by RP HPLC on (C18 Sunfire 30 ⁇ 100 5 ⁇ m).
• the desired product was prepared in an analogous manner to example 108 (using trifluoracetic anhydride instead of difluoroacetic anhydride in Step) and was purified via basic HPLC (Agilent prep system, Waters XBridge C18 5 um 50 ⁇ 100 mm column, 5-95% MeCN/20 nM NH 4 OH over 22 min at 80 mL/min) to provide the racemic product (6.8 mg, 25%).
• 1 H NMR 500 MHz, CDCl 3
• MS (ESI) mass mass calcd. C 20 H 13 ClF 6 N 4 O, 474.1; m/z found, 475.1 [M+H] + .
• the desired product was prepared in an analogous manner to example 53 (using cyclopropanecarbohydrazide instead of acetic hydrazide in Step F.)
• the racemic product was separated via chiral SFC (Stationary phase: CHIRALPAK AD-H 5 ⁇ m 250 ⁇ 20 mm), (Mobile phase: 70% CO 2 , 30% iPrOH) yielding the desired product.
• the desired product was prepared in an analogous manner to example 53 (using cyclopropanecarbohydrazide instead of acetic hydrazide in Step F.)
• the racemic product was separated via chiral SFC (Stationary phase: CHIRALPAK AD-H 5 ⁇ m 250 ⁇ 20 mm), (Mobile phase: 70% CO 2 , 30% iPrOH) yielding the desired product.
• the desired product was prepared in an analogous manner to example 53 (using pivalohydrazide instead of acetic hydrazide in Step F.)
• the racemic product was separated via chiral SFC (Stationary phase: CHIRALPAK AD-H 5 ⁇ m 250 ⁇ 20 mm), (Mobile phase: 80% CO 2 , 20% iPrOH) yielding the desired product.
• 1 H NMR 400 MHz, CDCl 3 ) ⁇ 7.86-7.71 (m, 1H), 7.60-7.28 (m, 7H), 6.20-6.01; 5.13-4.91 (m, 1H), 4.36-3.31 (m, 4H), 1.53-1.46 (m, 9H).
• MS (ESI) mass mass calcd. C 23 H 22 ClF 3 N 4 O, 462.1; m/z found, 463.1 [M+H] + .
• the desired product was prepared in an analogous manner to example 53 (using pivalohydrazide instead of acetic hydrazide in Step F.)
• the racemic product was separated via chiral SFC (Stationary phase: CHIRALPAK AD-H 5 ⁇ m 250 ⁇ 20 mm), (Mobile phase: 80% CO 2 , 20% iPrOH) yielding the desired product.
• 1 H NMR 400 MHz, CDCl 3 ) ⁇ 7.84-7.72 (m, 1H), 7.58-7.28 (m, 7H), 6.20-6.01; 5.12-4.96 (m, 1H), 4.34-3.29 (m, 4H), 1.53-1.45 (m, 9H).
• MS (ESI) mass mass calcd. C 23 H 22 ClF 3 N 4 O, 462.1; m/z found, 463.1 [M+H] + .
• the desired product was prepared in an analogous manner to example 53 (using oxazole-2-carbohydrazide instead of acetic hydrazide in Step F.)
• the racemic product was separated via chiral SFC (Stationary phase: CHIRALPAK AD-H 5 ⁇ m 250 ⁇ 20 mm), (Mobile phase: 68% CO 2 , 32% iPrOH) yielding the desired product.
• the desired product was prepared in an analogous manner to example 53 (using oxazole-2-carbohydrazide instead of acetic hydrazide in Step F.)
• the racemic product was separated via chiral SFC (Stationary phase: CHIRALPAK AD-H 5 ⁇ m 250 ⁇ 20 mm), (Mobile phase: 68% CO 2 , 32% iPrOH) yielding the desired product.
• the desired product was prepared in an analogous manner to example 53 (using propionohydrazide instead of acetic hydrazide in Step F.)
• the racemic product was separated via chiral SFC (Stationary phase: CHIRALPAK AD-H 5 ⁇ m 250 ⁇ 20 mm), (Mobile phase: 70% CO 2 , 30% iPrOH) yielding the desired product.
• 1 H NMR 400 MHz, CDCl 3 ) ⁇ 7.84-7.73 (m, 1H), 7.58-7.28 (m, 7H), 6.20-6.01; 5.19-5.02 (m, 1H), 4.17-3.30 (m, 4H), 2.89-2.64 (m, 2H), 1.49-1.37 (m, 3H).
• MS (ESI) mass mass calcd. C 21 H 18 ClF 3 N 4 O, 434.1; m/z found, 435.4 [M+H] + .
• the desired product was prepared in an analogous manner to example 53 (using propionohydrazide instead of acetic hydrazide in Step F.)
• the racemic product was separated via chiral SFC (Stationary phase: CHIRALPAK AD-H 5 ⁇ m 250 ⁇ 20 mm), (Mobile phase: 70% CO 2 , 30% iPrOH) yielding the desired product.
• 1 H NMR 400 MHz, CDCl 3 ) ⁇ 7.87-7.71 (m, 1H), 7.60-7.27 (m, 7H), 6.20-6.01; 5.19-5.01 (m, 1H), 4.16-3.28 (m, 4H), 2.88-2.67 (m, 2H), 1.48-1.39 (m, 3H).
• MS (ESI) mass mass calcd. C 21 H 18 ClF 3 N 4 O, 434.1; m/z found, 435.2 [M+H] + .
• the desired product was prepared in an analogous manner to example 53 (using isobutyrohydrazide instead of acetic hydrazide in Step F.)
• the racemic product was separated via chiral SFC (Stationary phase: CHIRALPAK AD-H 5 ⁇ m 250 ⁇ 20 mm), (Mobile phase: 70% CO 2 , 30% iPrOH) yielding the desired product.
• the desired product was prepared in an analogous manner to example 53 (using isobutyrohydrazide instead of acetic hydrazide in Step F.)
• the racemic product was separated via chiral SFC (Stationary phase: CHIRALPAK AD-H 5 ⁇ m 250 ⁇ 20 mm), (Mobile phase: 70% CO 2 , 30% iPrOH) yielding the desired product.
• the desired product was prepared in an analogous manner to example 108 (using trifluoracetic anhydride instead of difluoroacetic anhydride in Step C and 2,3-dichlorobenzoyl chloride instead of 2-chloro-3-(trifluoromethyl)benzoyl chloride in Step E) and was purified via basic HPLC (Agilent prep system, Waters XBridge C18 5 ⁇ m 50 ⁇ 100 mm column, 5-95% MeCN/20 nM NH 4 OH over 22 min at 80 mL/min) to provide the racemic product (100 mg, 55%).
• basic HPLC Agilent prep system, Waters XBridge C18 5 ⁇ m 50 ⁇ 100 mm column, 5-95% MeCN/20 nM NH 4 OH over 22 min at 80 mL/min
• the desired product was prepared in an analogous manner to example 85.
• the racemic product was separated via chiral SFC (Stationary phase: CHIRALPAK AD-H 5 ⁇ m 250 ⁇ 20 mm), (Mobile phase: 60% CO 2 , 40% iPrOH) yielding the desired product.
• 1 H NMR 400 MHz, CDCl 3 ) ⁇ 8.63-8.44 (m, 1H), 7.97-7.13 (m, 6H), 5.99-5.91; 5.26-5.10 (m, 1H), 4.50-3.52 (m, 4H), 2.51-2.43 (m, 3H).
• MS (ESI) mass mass calcd. C 19 H 15 ClF 3 N 5 O, 421.1; m/z found, 421.8 [M+H] + .
• the desired product was prepared in an analogous manner to example 85.
• the racemic product was separated via chiral SFC (Stationary phase: CHIRALPAK AD-H 5 ⁇ m 250 ⁇ 20 mm), (Mobile phase: 60% CO 2 , 40% iPrOH) yielding the desired product.
• 1 H NMR 400 MHz, CDCl 3 ) ⁇ 8.63-8.44 (m, 1H), 7.97-7.14 (m, 6H), 5.99-5.94; 5.24-5.10 (m, 1H), 4.49-3.53 (m, 4H), 2.52-2.41 (m, 3H).
• MS (ESI) mass mass calcd. C 19 H 15 ClF 3 N 5 O, 421.1; m/z found, 421.8 [M+H] + .
• the desired product was prepared in an analogous manner to example 53 (using cyclobutanecarbohydrazide instead of acetic hydrazide in Step F.)
• the racemic product was separated via chiral SFC (Stationary phase: CHIRALPAK AD-H 5 ⁇ m 250 ⁇ 20 mm), (Mobile phase: 70% CO 2 , 30% iPrOH) yielding the desired product.
• the desired product was prepared in an analogous manner to example 53 (using cyclobutanecarbohydrazide instead of acetic hydrazide in Step F.)
• the racemic product was separated via chiral SFC (Stationary phase: CHIRALPAK AD-H 5 ⁇ m 250 ⁇ 20 mm), (Mobile phase: 70% CO 2 , 30% iPrOH) yielding the desired product.
• Examples 95 and 96 were prepared as described in Example 108, substituting trifluoracetic anhydride for difluoroacetic anhydride in Step C and 2-chloro-4-fluoro-3-trifluoromethyl benzoic acid for 2-chloro-3-(trifluoromethyl)benzoic acid in Step E.
• the racemic mixture was separated by prep HPLC (Stationary phase: CHIRALPAK AD-H 5 ⁇ m 250 ⁇ 20mm), Mobile phase: 80% CO 2 , 20% EtOH) to provide the (R) and (S) enantiomers.
• the desired product was prepared in an analogous manner to example 108 (using trifluoracetic anhydride instead of difluoroacetic anhydride in Step C) and was separated via chrial SFC (Stationary phase: CHIRALPAK AD-H 5 ⁇ m 250 ⁇ 20 mm), (Mobile phase: 80% CO 2 , 20% iPrOH) yielding the desired product.
• 1 H NMR 400 MHz, CDCl 3 ) ⁇ 7.86-7.77 (m, 1H), 7.60-7.32 (m, 7H), 6.26-6.08; 5.23-5.09 (m, 1H), 4.40-3.36 (m, 4H).
• the desired product was separated from example 97 via chiral SFC (Stationary phase: CHIRALPAK AD-H 5 ⁇ m 250 ⁇ 20 mm), (Mobile phase: 80% CO 2 , 20% iPrOH) yielding the desired product.
• 1 H NMR 400 MHz, CDCl 3 ) ⁇ 7.86-7.76 (m, 1H), 7.60-7.31 (m, 7H), 6.26-6.07; 5.23-5.09 (m, 1H), 4.41-3.36 (m, 4H).
• MS (ESI) mass mass calcd. C 20 H 13 ClF 6 N 4 O, 474.1; m/z found, 474.8 [M+H] + .
• Examples 99 and 100 were prepared as described in Example 108, substituting trifluoracetic anhydride for difluoroacetic anhydride in Step C and 3-chloro-2-(trifluoromethyl)isonicotinic acid for 2-chloro-3-(trifluoromethyl)benzoic acid in Step E.
• the racemic mixture was separated by prep HPLC (Stationary phase: CHIRALPAK AD-H 5 ⁇ m 250 ⁇ 20mm), Mobile phase: 80% CO 2 , 20% EtOH) to provide the (R) and (S) enantiomers.
• the desired product was prepared in an analogous manner to example 108 (using trifluoracetic anhydride instead of difluoroacetic anhydride in Step C and 2,3-dichlorobenzoyl chloride instead of 2-chloro-3-(trifluoromethyl)benzoyl chloride in Step E) and was separated via chiral SFC (Stationary phase: CHIRALPAK AD-H 5 ⁇ m 250 ⁇ 20 mm), (Mobile phase: 75% CO 2 , 25% iPrOH) yielding the desired product.
• the desired product was separated from example 102 via chiral SFC (Stationary phase: CHIRALPAK AD-H 5 ⁇ m 250 ⁇ 20 mm), (Mobile phase: 75% CO 2 , 25% iPrOH) yielding the desired product.
• 1 H NMR 400 MHz, CDCl 3 ) ⁇ 7.61-7.53 (m, 1H), 7.53-7.19 (m, 7H), 6.33-6.12; 5.19-5.08 (m, 1H), 4.40-3.31 (m, 4H).
• MS (ESI) mass mass calcd. C 19 H 13 Cl 2 F 3 N 4 O, 440.0; m/z found, 440.8 [M+H] + .
• the desired product was prepared in an analogous manner to example 101 (using 2,3-dichlorobenzoyl chloride instead of 2-chloro-3-(trifluoromethyl)benzoyl chloride.)
• the racemic product was separated via chiral SFC (Stationary phase: CHIRALPAK AD-H 5 ⁇ m 250 ⁇ 20 mm), (Mobile phase: 75% CO 2 , 25% iPrOH) yielding the desired product.
• the desired product was prepared in an analogous manner to example 101 (using 2,3-dichlorobenzoyl chloride instead of 2-chloro-3-(trifluoromethyl)benzoyl chloride.)
• the racemic product was separated via chiral SFC (Stationary phase: CHIRALPAK AD-H 5 ⁇ m 250 ⁇ 20 mm), (Mobile phase: 75% CO 2 , 25% iPrOH) yielding the desired product.
• the desired product was prepared in an analogous manner to example 101 (using 3-cyclopropyl-8-(4-fluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine instead of 8-(4-fluorophenyl)-3-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine.)
• the racemic product was separated via chiral SFC (Stationary phase: CHIRALPAK AD-H 5 ⁇ m 250 ⁇ 20 mm), (Mobile phase: 75% CO 2 , 25% iPrOH) yielding the desired product.
• the desired product was prepared in an analogous manner to example 101 (using 3-cyclopropyl-8-(4-fluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine instead of 8-(4-fluorophenyl)-3-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine.)
• the racemic product was separated via chiral SFC (Stationary phase: CHIRALPAK AD-H 5 ⁇ m 250 ⁇ 20 mm), (Mobile phase: 75% CO 2 , 25% iPrOH) yielding the desired product.
• Step B 2-hydrazinyl-3-phenylpyrazine
• Step C 3-(difluoromethyl)-8-phenyl-[1,2,4]triazolo[4,3-a]pyrazine
• Step D 3-(difluoromethyl)-8-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine
• Step E (R)-(2-chloro-3-(trifluoromethyl)phenyl)(3-(difluoromethyl)-8-phenyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone
• the combined organic layers were dried using MgSO4 and concentrated into a residue, which was purified via basic HPLC (Agilent prep system, Waters XBridge C18 5 ⁇ m 50 ⁇ 100 mm column, 5-95% MeCN/20 nM NH 4 OH over 22 min at 80 mL/min) to provide the racemic product (132 mg, 48.2%).
• the racemic product was separated via chiral SFC (Stationary phase: CHIRALPAK AD-H 5 ⁇ m 250 ⁇ 20 mm), (Mobile phase: 70% CO 2 , 30% iPrOH) yielding the desired product.
• the desired product was separated from example 108 via chiral SFC (Stationary phase: CHIRALPAK AD-H 5 ⁇ m 250 ⁇ 20 mm), (Mobile phase: 70% CO 2 , 30% iPrOH) yielding the desired product.
• 1 H NMR 400 MHz, CDCl 3 ) ⁇ 7.87-7.76 (m, 1H), 7.60-7.30 (m, 7H), 7.14-6.84 (m, 1H), 3:1-6.09; 5.17-5.07 (m, 1H), 4.44-3.31 (m, 4H).
• MS (ESI) mass mass calcd. C 20 H 14 ClF 5 N 4 O, 456.1; m/z found, 456.8 [M+H] + .
• the desired product was prepared in an analogous manner to example 108 (using 2,3-dichlorobenzoyl chloride instead of 2-chloro-3-(trifluoromethyl)benzoyl chloride in Step E) and was separated via chiral SFC (Stationary phase: CHIRALPAK AD-H 5 ⁇ m 250 ⁇ 20 mm), (Mobile phase: 70% CO 2 , 30% iPrOH) yielding the desired product.
• 1 H NMR 400 MHz, CDCl 3 ) ⁇ 7.61-7.51 (m, 1H), 7.49-7.18 (m, 7H), 7.14-6.84 (m, 1H), 6.30-6.09; 5.15-5.08 (m, 1H), 4.44-3.28 (m, 4H).
• the desired product was separated from example 110 via chiral SFC (Stationary phase: CHIRALPAK AD-H 5 ⁇ m 250 ⁇ 20 mm), (Mobile phase: 70% CO 2 , 30% iPrOH) yielding the desired product.
• 1 H NMR 400 MHz, CDCl 3 ) ⁇ 7.61-7.51 (m, 1H), 7.50-7.18 (m, 7H), 7.14-6.84 (m, 1H), 3:1-6.09; 5.17-5.07 (m, 1H), 4.44-3.31 (m, 4H).
• the desired product was prepared in an analogous manner to example 85 (using 2,3-dichlorobenzoyl chloride instead of 2-chloro-3-(trifluoromethyl)benzoyl chloride.)
• the racemic product was separated via chiral SFC (Stationary phase: CHIRALPAK AD-H 5 ⁇ m 250 ⁇ 20 mm), (Mobile phase: 75% CO 2 , 25% iPrOH) yielding the desired product.
• 1 H NMR 400 MHz, CDCl 3 ) ⁇ 8.62-8.43 (m, 1H), 7.96-7.09 (m, 6H), 6.10-5.94; 5.20-5.07 (m, 1H), 4.45-3.57 (m, 4H), 2.52-2.39 (m, 3H).
• MS (ESI) mass mass calcd. C 18 H 15 Cl 2 N 5 O, 387.1; m/z found, 387.7 [M+H] + .
• the desired product was prepared in an analogous manner to example 85 (using 2,3-dichlorobenzoyl chloride instead of 2-chloro-3-(trifluoromethyl)benzoyl chloride.)
• the racemic product was separated via chiral SFC (Stationary phase: CHIRALPAK AD-H 5 ⁇ m 250 ⁇ 20 mm), (Mobile phase: 75% CO 2 , 25% iPrOH) yielding the desired product.
• 1 H NMR 400 MHz, CDCl 3 ) ⁇ 8.61-8.42 (m, 1H), 7.94-7.08 (m, 6H), 6.11-5.90; 5.22-5.07 (m, 1H), 4.46-3.57 (m, 4H), 2.54-2.41 (m, 3H).
• MS (ESI) mass mass calcd. C 18 H 15 Cl 2 N 5 O, 387.1; m/z found, 387.7 [M+H] + .
• the desired product was prepared in an analogous manner to example 101.
• the racemic product was separated via chiral SFC (Stationary phase: CHIRALPAK AD-H 5 ⁇ m 250 ⁇ 20 mm), (Mobile phase: 80% CO 2 , 20% iPrOH) yielding the desired product.
• 1 H NMR 400 MHz, CDCl 3 ) ⁇ 7.85-7.75 (m, 1H), 7.57-7.27 (m, 4H), 7.11-6.99 (m, 2H), 6.13-5.93; 5.20-5.07 (m, 1H), 4.15-3.27 (m, 4H), 2.52-2.43 (m, 3H).
• MS (ESI) mass mass calcd. C 20 H 15 ClF 4 N 4 O, 438.1; m/z found, 438.7 [M+H] + .
• the desired product was prepared in an analogous manner to example 101.
• the racemic product was separated via chiral SFC (Stationary phase: CHIRALPAK AD-H 5 ⁇ m 250 ⁇ 20 mm), (Mobile phase: 80% CO 2 , 20% iPrOH) yielding the desired product.
• 1 H NMR 400 MHz, CDCl 3 ) ⁇ 7.86-7.76 (m, 1H), 7.57-7.27 (m, 4H), 7.11-6.99 (m, 2H), 6.12-5.94; 5.20-5.04 (m, 1H), 4.15-3.26 (m, 4H), 2.53-2.41 (m, 3H).
• MS (ESI) mass mass calcd. C 20 H 15 ClF 4 N 4 O, 438.1; m/z found, 438.7 [M+H] ⁇ .
• the desired product was prepared in an analogous manner to example 101 (using 2-methyl-3-(trifluoromethyl)benzoyl chloride instead of 82-chloro-3-(trifluoromethyl)benzoyl chloride.)
• the racemic product was separated via chiral SFC (Stationary phase: CHIRALPAK AD-H 5 ⁇ m 250 ⁇ 20 mm), (Mobile phase: 75% CO 2 , 25% iPrOH) yielding the desired product.
• the desired product was prepared in an analogous manner to example 101 (using 2-methyl-3-(trifluoromethyl)benzoyl chloride instead of 82-chloro-3-(trifluoromethyl)benzoyl chloride.)
• the racemic product was separated via chiral SFC (Stationary phase: CHIRALPAK AD-H 5 ⁇ m 250 ⁇ 20 mm), (Mobile phase: 75% CO 2 , 25% iPrOH) yielding the desired product.
• the desired product was prepared in an analogous manner to example 108 (using trifluoracetic anhydride instead of difluoroacetic anhydride in Step C and 2-chloro-4-fluorobenzoyl chloride instead of 2-chloro-3-(trifluoromethyl)benzoyl chloride in Step E) and was separated via chiral SFC (Stationary phase: CHIRALPAK AD-H 5 ⁇ m 250 ⁇ 20 mm), (Mobile phase: 70% CO 2 , 30% iPrOH) yielding the desired product.
• the desired product was separated from example 118 via chiral SFC (Stationary phase: CHIRALPAK AD-H 5 ⁇ m 250 ⁇ 20 mm), (Mobile phase: 70% CO 2 , 30% iPrOH) yielding the desired product.
• 1 H NMR 500 MHz, CDCl 3 ) ⁇ 7.55-7.46 (m, 1H), 7.45-7.01 (m, 7H), 6.17-6.09; 5.18-5.10 (m, 1H), 4.36-3.33 (m, 4H).
• MS (ESI) mass mass calcd. C 19 H 13 ClF 4 N 4 O, 424.1; m/z found, 424.7 [M+H] + .
• the desired product was prepared in an analogous manner to example 108 (using trifluoracetic anhydride instead of difluoroacetic anhydride in Step C and 2,4-dichlorobenzoyl chloride instead of 2-chloro-3-(trifluoromethyl)benzoyl chloride in Step E) and was separated via chiral SFC (Stationary phase: CHIRALPAK AD-H 5 ⁇ m 250 ⁇ 20 mm), (Mobile phase: 70% CO 2 , 30% iPrOH) yielding the desired product.
• the desired product was separated from example 120 via chiral SFC (Stationary phase: CHIRALPAK AD-H 5 ⁇ m 250 ⁇ 20 mm), (Mobile phase: 70% CO 2 , 30% iPrOH) yielding the desired product.
• 1 H NMR 400 MHz, CDCl 3 ) ⁇ 7.54-7.47 (m, 1H), 7.47-7.29 (m, 7H), 6.15-6.09; 5.17-5.08 (m, 1H), 4.37-3.31 (m, 4H).
• MS (ESI) mass mass calcd. C 19 H 13 Cl 2 F 3 N 4 O, 440.0; m/z found, 440.7 [M+H] + .
• the desired product was prepared in an analogous manner to example 108 (using trifluoracetic anhydride instead of difluoroacetic anhydride in Step C and 2-methyl-3-(trifluoromethyl)benzoyl chloride instead of 2-chloro-3-(trifluoromethyl)benzoyl chloride in Step E) and was separated via chiral SFC (Stationary phase: CHIRALPAK AD-H 5 ⁇ m 250 ⁇ 20 mm), (Mobile phase: 80% CO 2 , 20% iPrOH) yielding the desired product.
• the desired product was separated from example 122 via chiral SFC (Stationary phase: CHIRALPAK AD-H 5 ⁇ m 250 ⁇ 20 mm), (Mobile phase: 80% CO 2 , 20% iPrOH) yielding the desired product.
• 1 H NMR 400 MHz, CDCl 3 ) ⁇ 7.78-7.67 (m, 1H), 7.60-7.28 (m, 7H), 6.33-6.06; 5.26-5.14 (m, 1H), 4.43-3.37 (m, 4H), 2.51-2.16 (m, 3H).
• MS (ESI) mass mass calcd. C 21 H 16 F 6 N 4 O, 454.1; m/z found, 454.8 [M+H] + .
• the desired product was prepared in an analogous manner to example 108 (using trifluoracetic anhydride instead of difluoroacetic anhydride in Step C and 2,3-dichloro-4-fluorobenzoyl chloride instead of 2-chloro-3-(trifluoromethyl)benzoyl chloride in Step E) and was separated via chiral SFC (Stationary phase: CHIRALPAK AD-H 5 ⁇ m 250 ⁇ 20 mm), (Mobile phase: 75% CO 2 , 25% iPrOH) yielding the desired product.
• the desired product was separated from example 124 via chiral SFC (Stationary phase: CHIRALPAK AD-H 5 ⁇ m 250 ⁇ 20 mm), (Mobile phase: 75% CO 2 , 25% iPrOH) yielding the desired product.
• 1 H NMR 400 MHz, CDCl 3 ) ⁇ 7.52-7.46 (m, 1H), 7.44-7.11 (m, 6H), 6.33-6.08; 5.17-5.09 (m, 1H), 4.39-3.32 (m, 4H).
• MS (ESI) mass mass calcd. C 19 H 12 Cl 2 F 4 N 4 O, 458.0; m/z found, 458.7 [M+H] + .
• the desired product was prepared in an analogous manner to example 108 (using 1-(2-tetrahydropyranyl)-1H-pyrazole-5-boronic acid pinacol ester instead of phenylboronic acid in Step A and trifluoracetic anhydride instead of difluoroacetic anhydride in Step C) and was purified via basic HPLC (Agilent prep system, Waters XBridge C18 5 ⁇ m 50 ⁇ 100 mm column, 5-95% MeCN/20 nM NH 4 OH over 22 min at 80 mL/min) yielding the desired product.
• basic HPLC Alent prep system, Waters XBridge C18 5 ⁇ m 50 ⁇ 100 mm column, 5-95% MeCN/20 nM NH 4 OH over 22 min at 80 mL/min
• the desired product was prepared in an analogous manner to example 108 (using 1-(2-tetrahydropyranyl)-1H-pyrazole-5-boronic acid pinacol ester instead of phenylboronic acid in Step A and trifluoracetic anhydride instead of difluoroacetic anhydride in Step C) and was purified via basic HPLC (Agilent prep system, Waters XBridge C18 5 ⁇ m 50 ⁇ 100 mm column, 5-95% MeCN/20 nM NH 4 OH over 22 min at 80 mL/min) yielding the desired product.
• basic HPLC Alent prep system, Waters XBridge C18 5 ⁇ m 50 ⁇ 100 mm column, 5-95% MeCN/20 nM NH 4 OH over 22 min at 80 mL/min
• the desired product was prepared in an analogous manner to example 108 (using trifluoracetic anhydride instead of difluoroacetic anhydride in Step C and 2-fluoro-3-(trifluoromethyl)benzoyl chloride instead of 2-chloro-3-(trifluoromethyl)benzoyl chloride in Step E) and was separated via chiral SFC (Stationary phase: CHIRALPAK AD-H 5 ⁇ m 250 ⁇ 20 mm), (Mobile phase: 85% CO 2 , 15% iPrOH) yielding the desired product.
• Step A 6-methyl-8-phenyl-3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine
• the desired product was prepared in an analogous manner to example 108 (using 2,3-dichloro-5-methylpyrazine instead of 2,3-dichloropyrazine in Step A and trifluoracetic anhydride instead of difluoroacetic anhydride in Step C) yielding the desired product (502 mg, 46%).
• Step 130B ( ⁇ )-(2-chloro-3-(trifluoromethyl)phenyl)(6-methyl-8-phenyl-3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone
• Step A 3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine 7-oxide
• Step B 8-benzyl-3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-ol
• Step C 8-benzyl-3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine
• Step D (8-benzyl-3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(2-chloro-3-(trifluoromethyl)phenyl)methanone
• HPLC analysis was performed on a LaChrom Elite HPLC system (Hitachi, Armstadt, Germany) connected to a UV spectrometer set at 220 nm.
• the HPLC eluate after passage through the UV detector, was led over a shielded 3-inch NaI(Tl) scintillation detector connected to a multichannel analyser (Gabi box, Raytest, Straubenhardt, Germany).
• the output signal was recorded and analysed using a GINA Star data acquisition system (Raytest, Straubenhardt, Germany).
• Radioactivity in samples of biodistribution studies, cell uptake experiments and radiometabolite analysis was quantified using an automated gamma counter equipped with a 3-inch NaI(Tl) well crystal coupled to a multichannel analyser (Wallac 2480 Wizard, Wallac, Turku, Finland). Results were corrected for background radiation, physical decay and counter dead time.

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